TARGET: Cardiac Arrythmias
   
 

DISEASE STATE

Cardiac arrhythmias are disorders of the heart rhythm that are manifested as an irregular heartbeat or a heartbeat that is faster or slower than normal. These arrhythmias can arise in the lower chambers (ventricles) or upper chambers (atria) of the heart. They may result in palpitations, fatigue, fainting, and dizziness and are considered key risk factors for stroke and sudden cardiac death.
  Ventricular arrhythmias can sometimes lead to ventricular fibrillation, a condition in which the ventricles beat rapidly and erratically. As a result, the heart does not effectively pump blood to the body. If untreated, ventricular fibrillation can be fatal in minutes.
  During atrial fibrillation, the heart fails to effectively pump blood out of the upper chambers of the heart, creating a risk that the blood will pool and clot. If a blood clot formed in the atria leaves the heart and becomes lodged in an artery in the brain, a stroke results.
   
 

PREVALENCE

An estimated >400,000 people in the United States die of ventricular arrhythmias every year.
  Atrial fibrillation occurs in an estimated 2.5-5.5 million people in the United States and 5.5 million people in Japan and Western Europe. It is the most common arrhythmia.
  About 15% of strokes occur in people with atrial fibrillation. The likelihood of developing atrial fibrillation increases with age, and the prevalence of this disorder is estimated to double during each decade between the ages of 50 and 90.
   
 

THE ROLE OF RYCAL™ COMPOUNDS IN CARDIAC ARRYTHMIAS

Rycal™ compounds provide a new approach to the treatment of potentially life-threatening cardiac arrhythmias. Rycal™ compounds enhance the binding of the stabilizing subunit calstabin2 to the RyR2 channels and inhibit pathological diastolic sarcoplasmic reticulum calcium leak, but they do NOT block the RyR2 channels. Moreover, they have no measurable action against normal, non-leaky channels. Instead, they restore the function of defective leaky channels. Leaky RyR2 channels have been implicated in exercise-induced arrhythmias and in atrial fibrillation.
   
 

CLINICAL STATUS

In preclinical studies, Rycal™ compounds suppressed ventricular arrhythmias and sudden cardiac death. No toxicities have been observed even at doses that exceed the therapeutic doses.
 
 
Wehrens X, Lehnart SE, Reiken SR, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell. 2003;113:829-840.
 
Wehrens T, Lehnart S, Reiken S, et al. Protection from cardiac arrhythmias through ryanide receptor–stabilizing protein calstabin2. Science. 2004;304:292-296.
  
 
Vest JA, Reiken, SR, Wehrens, XHT, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation. 2005;111;2025-2032.
   

Current News


 

ARMGO™ Pharma Receives $1 Million Award from MDA to Support Advancement of Rycal™ Compound ARM210 as a Novel Treatment for Duchenne Muscular Dystrophy   Link to Article

 

ARMGO™ Pharma, Inc. announces the appointment of Dr. Sapan Shah as CEO   Link to Article

 

Kushnir A, Marks AR. The ryanodine receptor in cardiac physiology and disease. Adv Pharmacol. 2010;59:1-30.   Link to Article

 

Kushnir A, Shan J, Betzenhauser MJ, Reiken S, Marks AR. Role of CaMKlldelta phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure. Proc Natl Acad Sci U S A. 2010 Jun1;107(22):10274-9.   Link to Article

 

Kushnir A, Betzenhauser MJ, Marks AR. Ryanodine receptor studies using genetically engineered mice.FEBS Lett. 2010 May 17;584(10):1956-65.   Link to Article

 

Betzenhauser MJ, Marks AR. Ryanodine Receptor channelopathies Pflugers Arch. 2010 Jul;460(2):467-80.   Link to Article

 

Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR,Lacampagne A.- Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1559-64.4-9.   Link to Article

Prof. Andrew Marks presentation on, "Mechanism-Based Therapies for Heart Failure and Cardiac Arrhythmias" from the Henry Stewart Talks, Series, "Calcium Signalling: Regulation, Mechanisms, Effectors, Role in Disease and Recent Advances".
Link to Presentation